OVERALL SUMMARY. Major depressive disorder (MDD) topped heart disease as the number one cause of disability worldwide, and women have twice the risk of men. MDD is associated with abnormalities in the stress response circuitry, areas that are among the most sexually dimorphic in the brain. These areas are dense in sex steroid and glucocorticoid receptors coupled with cytokine receptors. Further, activity in these areas has been associated with cortisol response, autonomic dysfunction, and immune responses, which we showed differed by sex. This is important since autonomic dysregulation is significantly associated with cardiovascular disease. In fact, women are at twice the risk for the co-occurrence of MDD, autonomic dysregulation and heart disease, leading to a 3-5-fold risk of death in women from heart disease, often with unrecognized and untreated MDD. Thus, understanding early biomarkers for sex differences in MDD and autonomic dysregulation will provide knowledge for early intervention, attenuating later life disability, in particular for women who are at higher risk. The scientific mission of this SCORE is to identify stress-immune pathway abnormalities, beginning in fetal development, that have shared consequences for sex differences in brain circuitry regulating mood and lifelong recurrent MDD and dysregulation of hormone and immune responses to stress, and autonomic and neurovascular dysfunction in early midlife. We aim to facilitate transdisciplinary, translational collaboration among basic and clinical investigators to enhance our understanding of the impact of sex on MDD and central and peripheral autonomic function and provide the groundwork for translating this knowledge into sex-selective therapeutics. Further, we aim to serve as an interdisciplinary resource to train and disseminate findings about sex differences in MDD and autonomic dysregulation to the scientific and medical communities, policy makers, and the public. To accomplish this, three integrated studies are proposed: 1) a clinical population neuroscience study relating prenatal risk biomarkers to sex differences in brain circuitry and physiologic deficits in response to stress in MDD in early midlife; 2) clinical study using direct transcutaneous neuromodulatory stimulation of the vagus nerve, auricular branch (or taVNS) to target the circuitry associated with stress-immune function and map its neuroanatomic, physiologic and clinical effects in MDD by sex, in the same subjects as in project 1; and 3) rodent model studies that will map out the central mechanistic pathways involved in projects 1 and 2. In addition, three cores will contribute to the success of this SCORE: 1) Leadership Administration Core to administer and oversee the administrative integration of the studies and cores; 2) Resources Core to provide shared technical expertise across studies; and 3) Career Enhancement Core, to supplement the training of junior faculty and others on the topic of our SCORE, and become pedagogical ambassadors to the scientific, medical and public communities about sex differences in depression and comorbidities with general medicine, a topic with global public health implications.